Tubular basement membrane damage promotes renal fibrosis via an ETV5/TGFB1/SOX9 axis in proximal tubular epithelial cells after acute kidney injury.

The interaction between injured proximal tubular epithelial cells (PTECs) and the microenvironment has been widely associated with post-AKI fibrosis; however, the underlying mechanisms remain largely unclear. In this study, we identified three distinct injury patterns of the tubular basement membrane (TBM) in kidney tissues from patients with acute kidney injury. Phosphorylated H3Ser10 and transforming growth factor-β1 (TGFB1) were co-localized in PTECs exhibiting TBM injury. To mimic this condition, we employed a low-attachment culture system (LACS). LACS induced in PTECs a morphology resembling that of maladaptive repaired PTECs, accompanied by G2/M cell-cycle arrest, as well as upregulation and secretion of TGFB1. The expression of TGFB1 was markedly suppressed when PTECs were re-attached to normal culture dishes or to medium supplemented with Matrigel. Furthermore, TGFB1 expression was not directly linked to G2/M arrest in PTECs. Mechanistically, knockdown of TGFB1 or SMAD3 attenuated the LACS-induced upregulation of SOX9, whereas SOX9 knockdown did not downregulate TGFB1 expression. We further demonstrated that TBM injury-induced upregulation of TGFB1 is mediated by ETV5. Collectively, these findings indicate that TBM damage triggered by AKI promotes renal fibrosis via activation of the ETV5/TGFB1/SMAD3/SOX9 pathway in proximal tubular epithelial cells following AKI.